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This medical PowerPoint presentation is about radiopharmaceuticals and the methods of radiolabeling.

Radiopharmaceuticals are drugs that contain radioactive isotopes and are used for diagnostic or therapeutic purposes in medicine. Radiolabeling is the process of attaching a radioactive isotope to a molecule, usually a drug, to create a radiopharmaceutical.

There are several methods of radiolabeling, including:
Radioiodination: This involves attaching radioactive iodine to a molecule. It is commonly used in the production of thyroid function tests.
Radiometal labeling: This involves attaching a radioactive metal to a molecule, such as technetium-99m (Tc-99m) or gallium-68 (Ga-68). These radiometals are commonly used in positron emission tomography (PET) scans and single-photon emission computed tomography (SPECT) scans.
Radiolabeling with fluorine-18: This involves attaching a radioactive fluorine isotope to a molecule. It is commonly used in PET scans.
Radiolabeling with carbon-11: This involves attaching a radioactive carbon isotope to a molecule. It is commonly used in PET scans.

The choice of radiolabeling method depends on the specific molecule being labeled, the desired imaging or therapeutic application, and the available resources for producing and handling the radiopharmaceutical.

Tags : radiopharmaceuticals, methods of radiolabeling, radioactive isotopes, Radioiodination, Radiometal labeling, Radiolabeling with fluorine-18, Radiolabeling with carbon-11, Nuclear Medicine, Nuclear Medicine PowerPoint presentation

Published on : Jun 20, 2023 | Views : 978 | Downloads : 1

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Slide 1-

Radiopharmaceuticals andMethods of Radiolabeling
Slide 2-

Definition of a Radiopharmaceutical
Slide 3-

Definition of a Radiopharmaceutical A radiopharmaceutical is a radioactive compound used for the diagnosis and therapeutic treatment of human diseases. In nuclear medicine nearly 95% of the radiopharmaceuticals are used for diagnostic purposes, while the rest are used for therapeutic treatment. Radiopharmaceuticals usually have minimal pharmacologic e¤ect, because in most cases they are used in tracer quantities. Therapeutic radiopharmaceuticals can cause tissue damage by radiation.
Slide 4-

Definition of a Radiopharmaceutical Because they are administered to humans, they should be sterile and pyrogen free, and should undergo all quality control measures required of a conventional drug. A radiopharmaceutical may be a radioactive element such as 133Xe, or a labeled compound such as 131I-iodinated proteinsand 99mTc-labeled compounds.
Slide 5-

Definition of a Radiopharmaceutical Although the term radiopharmaceutical is most commonly used, other terms such as radiotracer, radiodiagnostic agent, and tracer have been used by various groups. We shall use the term radiopharmaceutical throughout, although the term tracer will be used occasionally.
Slide 6-

Definition of a Radiopharmaceutical Another point of interest is the di¤erence between radiochemicals and radiopharmaceuticals. The former are not usable for administration to humans due to the possible lack of sterility and nonpyrogenicity. On the other hand, radiopharmaceuticals are sterile and nonpyrogenic and can be administered safely to humans.
Slide 7-

Definition of a Radiopharmaceutical A radiopharmaceutical has two components: a radionuclide and a pharmaceutical. The usefulness of a radiopharmaceutical is dictated by the characteristics of these two components. In designing a radiopharmaceutical, a pharmaceutical is first chosen on the basis of its preferential localization in a given organ or its participation in the physiologic function of the organ.
Slide 8-

Definition of a Radiopharmaceutical Then a suitable radionuclide is tagged onto the chosen pharmaceutical such that after administration of the radiopharmaceutical, radiations emitted from it are detected by a radiation detector. Thus, the morphologic structure or the physiologic function of the organ can be assessed. The pharmaceutical of choice should be safe and nontoxic for human administration.
Slide 9-

Definition of a Radiopharmaceutical Radiations from the radionuclide of choice should be easily detected by nuclear instruments,and the radiation dose to the patient should be minimal.
Slide 10-

Ideal Radiopharmaceutical
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Ideal Radiopharmaceutical Since radiopharmaceuticals are administered to humans, and because there are several limitations on the detection of radiations by currently available instruments, radiopharmaceuticals should possess some important characteristics. The ideal characteristics for radiopharmaceuticals are:
Slide 12-

Ideal Radiopharmaceutical 1. Easy Availability The radiopharmaceutical should be easily produced, inexpensive, and readily available in any nuclear medicine facility Complicated methods of production of radionuclides or labeled compounds increase the cost of the radiopharmaceutical. The geographic distance between the user and the supplier also limits the availability of short-lived radiopharmaceuticals.
Slide 13-

Ideal Radiopharmaceutical 2. Short Effective Half-Life A radionuclide decays with a definite half-life, which is called the physical half-life, denoted Tp (or t1=2). The physical half-life is independent of any physicochemical condition and is characteristic for a given radionuclide
Slide 14-

Ideal Radiopharmaceutical 2. Short Effective Half-Life (cont,..) Radiopharmaceuticals administered to humans disappear from the biological system through fecal or urinary excretion, perspiration, or other mechanisms. This biologic disappearance of a radiopharmaceutical follows an exponential law similar to that of radionuclide decay. Thus, every radiopharmaceutical has a biologic half-life (Tb). It is the time needed for half of the radiopharmaceutical to disappear from the biologic system and therefore is related to a decay constant= 0.693/λ= TP
Slide 15-

Ideal Radiopharmaceutical 2. Short Effective Half-Life (cont,..) Obviously, in any biologic system, the loss of a radiopharmaceutical is due to both the physical decay of the radionuclide and the biologic elimination of the radiopharmaceutical.
Slide 16-

Ideal Radiopharmaceutical 2. Short Effective Half-Life (cont,..) The net or e¤ective rate (le) of the loss of radioactivity is then related to the physical decay constant lp and the biologic decay constant lb. Mathematically, this is expressed as: λe = λp ‏ + λb Since λ = 0.693/t1/2, it follows that 1/Te = 1/Tp + ‏1/Tb OR Te = ( Tp X Tb) / ( Tp +‏ Tb )
Slide 17-

Problem 6.1 The physical half-life of 111In is 67 hr and the biologic half-life of 111In-DTPA used for measurement of the glomerular filtration rate is 1.5 hr. What is the e¤ective half-life of 111In-DTPA? Answer Using Eq. (6.3), Te ¼ 1:5 67 67 ‏ 1:5 ¼ 100:5 68:5 ¼ 1:47 hr Radiopharmaceuticals
Slide 18-

Ideal Radiopharmaceutical 3. Particle Emission Radionuclides decaying by a- or b-particle emission should not be used as the label in diagnostic radiopharmaceuticals. These particles cause more radiation damage to the tissue than do g rays. Although g-ray emission is preferable, many b-emitting radionuclides, such as 131I-iodinated compounds, are often used for clinical studies.
Slide 19-

Ideal Radiopharmaceutical 3. Particle Emission (cont,..) However, a emitters should never be used for in vivo diagnostic studies because they give a high radiation dose to the patient. But a and b emitters are useful for therapy, because of the effective radiation damage to abnormal cells.
Slide 20-

Ideal Radiopharmaceutical 4. Decay by Electron Capture or Isomeric Transition Because radionuclides emitting particles are less desirable, the diagnostic radionuclides used should decay by electron capture or isomeric transition without any internal conversion. Whatever the mode of decay, for diagnostic studies the radionuclide must emit a Ɣ radiation with an energy preferably between 30 and 300 keV. Below 30 keV, Ɣ rays are absorbed by tissue
Slide 21-

Ideal Radiopharmaceutical Photon interaction in the NaI(T1) detector using collimators. A 30-keV photon is absorbed by the tissue. A> 300-keV photon may penetrate through the collimator septa and strike the detector, or may escape the detector without any interaction. Photons of 30 to 300 keV may escape the organ of the body, pass through the collimator holes, and interact with the detector.
Slide 22-

Ideal Radiopharmaceutical 4. Decay by Electron Capture or Isomeric Transition (cont,..) and are not detected by the NaI(Tl) detector. Above 300 keV, e¤ective collimation of g rays cannot be achieved with commonly available collimators. However, recently manufacturers have made collimators for 511-keV photons, which have been used for planar or SPECT imaging using 18FFDG. The phenomenon of collimation with 30- to 300-keV photons is illustrated approximately 150 keV, which is most suitable for present-day collimators. Moreover, the photon abundance should be high so that imaging time can be minimized due to the high photon flux.
Slide 23-

Ideal Radiopharmaceutical 5. High Target-to-Nontarget Activity Ratio For any diagnostic study, it is desirable that the radiopharmaceutical be localized preferentially in the organ under study since the activity from nontarget areas can obscure the structural details of the picture of the target organ. Therefore, the target-to-nontarget activity ratio should be large.
Slide 24-

Ideal Radiopharmaceutical 5. High Target-to-Nontarget Activity Ratio (cont,..) An ideal radiopharmaceutical should have all the above characteristics to provide maximum effcacy in the diagnosis of diseases and a minimum radiation dose to the patient. However, it is diffcult for a given radiopharmaceutical to meet all these criteria and the one of choice is the best of many compromises.
Slide 25-

Design of New Radiopharmaceuticals
Slide 26-

General Considerations Many radiopharmaceuticals are used for various nuclear medicine tests. Some of them meet most of the requirements for the intended test andtherefore need no replacement. For example, 99mTc–methylene diphosphonate (MDP) is an excellent bone imaging agent and the nuclear medicine community is fairly satisfied with this agent such that no further research and development is being pursued for replacing 99mTc-MDP with a new radiopharmaceutical.
Slide 27-

General Considerations (cont,..) However, there are a number of other radio pharmaceuticalthat o¤er only minimal diagnostic value in nuclear medicine tests and thus need replacement. Continual effort is being made to improve or replace such radiopharmaceuticals.
Slide 28-

General Considerations (cont,..) Upon scrutiny, it is noted that the commonly used radiopharmaceuticals involve one or more of the following mechanisms of localization in a given organ: Passive di¤usion: 99mTc-DTPA in brain imaging, 99mTc-DTPA aerosol and 133Xe in ventilation imaging, 111In-DTPA in cisternography. Ion exchange: uptake of 99mTc-phosphonate complexes in bone.
Slide 29-

General Considerations (cont,..) 3. Capillary blockage: 99mTc macroaggregated albumin (MAA) particles trapped in the lung capillaries. 4. Phagocytosis: removal of 99mTc-sulfur colloid particles by the reticuloendothelial cells in the liver, spleen, and bone marrow. 5. Active transport: 131I uptake in the thyroid, 201Tl uptake in the myocardium. 6. Cell sequestration: sequestration of heat-damaged 99mTc-labeled red blood cells by the spleen.
Slide 30-

General Considerations (cont,..) 7. Metabolism: 18F-FDG uptake in myocardial and brain tissues. 8. Receptor binding: 11C-dopamine binding to the dopamine receptors in the brain. 9. Compartmental localization: 99mTc-labeled red blood cells used in the gated blood pool study. 10. Antigen-antibody complex formation: 131I-, 111In-, and 99mTc-labeled antibody to localize tumors. 11. Chemotaxis: 111In-labeled leukocytes to localize infections.
Slide 31-

General Considerations (cont,..) Based on these criteria, it is conceivable to design a radiopharmaceutical to evaluate the function and/or structure of an organ of interest. Once a radiopharmaceutical is conceptually designed, a definite protocol should be developed based on the physicochemical properties of the basic ingredients to prepare the radiopharmaceutical.
Slide 32-

General Considerations (cont,..) The method of preparation should be simple, easy, and reproducible, and should not alter the desired property of the labeled compound. Optimum conditions of temperature, pH, ionic strength, and molar ratios should be established and maintained for maximum effcacy of the radiopharmaceutical.
Slide 33-

General Considerations (cont,..) Once a radiopharmaceutical is developed and successfully formulated, its clinical effcacy must be evaluated by testing it first in animals and then in humans. For use in humans, one has to have a Notice of Claimed Investigational Exemption for a New Drug (IND) from the U.S. Food and Drug Administration (FDA), which regulates the human trials of drugs very strictly. If there is any severe adverse e¤ect in humans due to the administration of a radiopharmaceutical, then the radiopharmaceutical is discarded.
Slide 34-

Factors Influencing the Design of NewRadiopharmaceuticals The following factors need to be considered before, during, and after the preparation of a new radiopharmaceutical.
Slide 35-

Factors Influencing the Design of NewRadiopharmaceuticals
Slide 36-

Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
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Factors Influencing the Design of NewRadiopharmaceuticals
Slide 53-

Factors Influencing the Design of NewRadiopharmaceuticals
Slide 54-

Factors Influencing the Design of NewRadiopharmaceuticals
Slide 55-

Factors Influencing the Design of NewRadiopharmaceuticals
Slide 56-

Methods of Radiolabeling
Slide 57-

Methods of Radiolabeling The use of compounds labeled with radionuclides has grown considerably in medical, biochemical, and other related fields. In the medical field, compounds labeled with β-emitting radionuclides are mainly restricted to in vitro experiments and therapeutic treatment, whereas those labeled with ɤemitting radionuclides have much wider applications. The latter are particularly useful for in vivo imaging of different organs.
Slide 58-

Methods of Radiolabeling (cont,..) These methods and various factors a¤ecting the labeled compounds are discussed below.
Slide 59-

Isotope Exchange Reactions In isotope exchange reactions, one or more atoms in a molecule are replaced by isotopes of the same element having different mass numbers. Since the radiolabeled and parent molecules are identical except for the isotope e¤ect, they are expected to have the same biologic and chemical properties. Examples are 125I-triiodothyronine (T3), 125I-thyroxine (T4), and 14C-, 35S-, and 3H-labeled compounds. These labeling reactions are reversible and are useful for labeling iodine-containing material with iodine radioisotopes and for labeling many compounds with tritium.
Slide 60-

Introduction of a Foreign Label In this type of labeling, a radionuclide is incorporated into a molecule that has a known biologic role, primarily by the formation of covalent or coordinate covalent bonds. The tagging radionuclide is foreign to the molecule and does not label it by the exchange of one of its isotopes. Some examples are 99mTc-labeled albumin, 99mTc-DTPA, 51Cr-labeled red blood cells, and many iodinated proteins and enzymes. In several instances, the in vivo stability of the material is uncertain and one should be cautious about any alteration in the chemical and biologic properties of the labeled compound.
Slide 61-

Introduction of a Foreign Label (cont,…) In many compounds of this category, the chemical bond is formed by chelation, that is, more than one atom donates a pair of electrons to the foreign acceptor atom, which is usually a transition metal. Most of the 99mTc-labeled compounds used in nuclear medicine are formed by chelation. For example, 99mTc binds to DTPA, gluceptate, and other ligads by chelation.
Slide 62-

Labeling with Bifunctional Chelating Agents In this approach, a bifunctional chelating agent is conjugated to a macromolecule (e.g., protein, antibody) on one side and to a metal ion (e.g., Tc) by chelation on the other side. Examples of bifunctional chelating agents are DTPA, metallothionein, diamide dimercaptide (N2S2), hydrazinonicotinamide (HYNIC) and dithiosemicarbazone.
Slide 63-

Labeling with Bifunctional Chelating Agents (cont,…) There are two methods—the preformed 99mTc chelate method and the indirect chelator-antibody method. In the preformed 99mTc chelate method, 99mTc chelates are initially preformed using chelating agents such as diamidodithiol, cyclam, and so on, which are then used to label macromolecules by forming bonds between the chelating agent and the protein.
Slide 64-

Labeling with Bifunctional Chelating Agents (cont,…) In contrast, in the indirect method, the bifunctional chelating agent is initially conjugated with a macromolecule, which is then allowed to react with a metal ion to form a metal-chelate-macromolecule complex. Various antibodies are labeled by the latter method. Because of the presence of the chelating agent, the biological properties of the labeled protein may be altered and must be assessed before clinical use.
Slide 65-

Labeling with Bifunctional Chelating Agents (cont,…) Although the prelabeled chelator approach provides a purer metalchelate complex with a more definite structural information, the method involves several steps and the labeling yield often is not optimal, thus favoring the chelatorantibody approach.
Slide 66-

Biosynthesis In biosynthesis, a living organism is grown in a culture medium containing the radioactive tracer, the tracer is incorporated into metabolites produced by the metabolic processes of the organism, and the metabolites are then chemically separated. For example, vitamin B12 is labeled with 60Co or 57Co by adding the tracer to a culture medium in which the organism Streptomyces griseus is grown. Other examples of biosynthesis include 14C-labeled carbohydrates, proteins, and fats.
Slide 67-

Recoil Labeling Recoil labeling is of limited interest because it is not used on a large scale for labeling. In a nuclear reaction, when particles are emitted from a nucleus, recoil atoms or ions are produced that can form a bond with other molecules present in the target material. The high energy of the recoil atoms results in poor yield and hence a low specific activity of the labeled product.
Slide 68-

Recoil Labeling (cont,..) Several tritiated compounds can be prepared in the reactor by the 6Li(n,α)3 reaction. The compound to be labeled is mixed with a lithium salt and irradiated in the reactor. Tritium produced in the above reaction labels the compound, primarily by the isotope exchange mechanism, and then the labeled compound is separated.
Slide 69-

Excitation Labeling Excitation labeling entails the utilization of radioactive and highly reactive daughter ions produced in a nuclear decay process. During b decay or electron capture, energetic charged ions are produced that are capable of labeling various compounds of interest. Krypton-77 decays to 77Br and, if the compound to be labeled is exposed to 77Kr, then energetic 77Br ions label the compound to form the brominated compound. Similarly, various proteins have been iodinated with 123I by exposing them to 123Xe, which decaysto 123I. The yield is considerably low with this method
Slide 70-

Important Factors in Labeling The majority of radiopharmaceuticals used in clinical practice are relatively easy to prepare in ionic, colloidal, macroaggregated, or chelated forms, and many can be made using commercially available kits. Several factors that influence the integrity of labeled compounds should be kept in mind. These factors are described briefly below.
Slide 71-

Important Factors in Labeling Efficiency of the Labeling Process A high labeling yield is always desirable, although it may not be attainable in many cases. However, a lower yield is sometimes acceptable if the product is pure and not damaged by the labeling method, the expense involved is minimal, and no better method of labeling is available.
Slide 72-

Important Factors in Labeling Chemical Stability of the Product Stability is related to the type of bond between the radionuclide and the compound. Compounds with covalent bonds are relatively stable under various physicochemical conditions. The stability constant of the labeled product should be large for greater stability.
Slide 73-

Important Factors in Labeling Denaturation or Alteration The structure and/or the biologic properties of a labeled compound can be altered by various physicochemical conditions during a labeling procedure. For example, proteins are denatured by heating, at pH below 2 and above 10, and by excessive iodination, and red blood cells are denatured by heating.
Slide 74-

Important Factors in Labeling Isotope Effect The isotope e¤ect results in di¤erent physical (and perhaps biologic) properties due to diferences in isotope weights. For example, in tritiated compounds,H atoms are replaced by 3H atoms and the diference in mass numbers of 3H and H may alter the property of the labeled compounds. It has been found that the physiologic behavior of tritiated water is different from that of normal water in the body. The isotope effect is not as serious when the isotopes are heavier.
Slide 75-

Important Factors in Labeling Carrier-Free or No-Carrier-Added (NCA) State Radiopharmaceuticals tend to be adsorbed on the inner walls of the containers if they are in a carrier-free or NCA state. Techniques have to be developed in which the labeling yield is not affected by the low concentration of the tracer in a carrier-free or NCA state.
Slide 76-

Important Factors in Labeling Storage Conditions Many labeled compounds are susceptible to decomposition at higher temperatures. Proteins and labeled dyes are degraded by heat and therefore should be stored at proper temperatures; for example, albumin should be stored under refrigeration. Light may also break down some labeled compounds and these should be stored in the dark. The loss of carrier-free tracers by adsorption on the walls of the container can be prevented by the use of silicon-coated vials.
Slide 77-

Important Factors in Labeling Specific Activity Specific activity is defined as the activity per gram of the labeled material. In many instances, high specific activity is required in the applications of radiolabeled compounds and appropriate methods should be devised to this end. In others, high specific activity can cause more radiolysis (see below) in the labeled compound and should be avoided.
Slide 78-

Important Factors in Labeling Radiolysis Many labeled compounds are decomposed by radiations emitted by the radionuclides present in them. This kind of decomposition is called radiolysis. The higher the specific activity, the greater the e¤ect of radiolysis. When the chemical bond breaks down by radiations from its own molecule, the process is termed ‘‘autoradiolysis. ’’ Radiations may also decompose the solvent, producing free radicals that can break down the chemical bond of the labeled compounds; this process is indirect radiolysis. For example, radiations from a labeled molecule can decompose water to produce hydrogen peroxide or perhydroxyl free radical, which oxidizes another labeled molecule. To help prevent indirect radiolysis, the pH of the solvent should be neutral because more reactions of this nature can occur at alkaline or acidic pH.
Slide 79-

Important Factors in Labeling Radiolysis ( cont,…) The longer the half-life of the radionuclide, the more extensive is the radiolysis, and the more energetic the radiations, the greater is the radiolysis. In essence, radiolysis introduces a number of radiochemical impurities in the sample of labeled material and one should be cautious about these unwanted products. These factors set the guidelines for the expiration date of a radiopharmaceutical.
Slide 80-

Important Factors in Labeling Purification and Analysis Radionuclide impurities are radioactive contaminants arising from the method of production of radionuclides. Fission is likely to produce more impurities than nuclear reactions in a cyclotron or reactor because fission of the heavy nuclei produces many product nuclides. Target impurities also add to the radionuclidic contaminants. The removal of radioactive contaminants can be accomplished by various chemical separation methods, usually at the radionuclide production stage.
Slide 81-

Important Factors in Labeling Purification and Analysis (cont,..) Radiochemical and chemical impurities arise from incomplete labeling of compounds and can be estimated by various analytical methods such as solvent extraction, ion exchange, paper, gel, or thin-layer chromatography, and electrophoresis. Often these impurities arise after labeling from natural degradation as well as from radiolysis.
Slide 82-

Important Factors in Labeling Shelf Life A labeled compound has a shelf life during which it can be used safely for its intended purpose. The loss of efficacy of a labeled compound over a period of time may result from radiolysis and depends on the physical half-life of the radionuclide, the solvent, any additive, the labeled molecule, the nature of emitted radiations, and the nature of the chemical bond between the radionuclide and the molecule. Usually a period of three physical half-lives or a maximum of 6 months is suggested as the limit for the shelf life of a labeled compound. The shelf-life of 99mTc-labeled compounds varies between 0.5 and 18 hr, the most common value being 6 hr.